Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo

Angew Chem Int Ed Engl. 2012 Aug 20;51(34):8529-33. doi: 10.1002/anie.201203263. Epub 2012 Jul 10.

Abstract

Special (lipid) delivery: The role of the ionizable lipid pK(a) in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pK(a) value and silencing of the mouse FVII gene (FVII ED(50) ) was found, with an optimal pK(a) range of 6.2-6.5. The most potent cationic lipid from this study has ED(50) levels around 0.005 mg kg(-1) in mice and less than 0.03 mg kg(-1) in non-human primates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry
  • Animals
  • Female
  • Gene Silencing*
  • Genetic Therapy / methods
  • Humans
  • Kinetics
  • Lipids / administration & dosage*
  • Lipids / chemistry
  • Liposomes / administration & dosage
  • Liposomes / chemistry
  • Liver / metabolism
  • Liver / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics*

Substances

  • Amines
  • Lipids
  • Liposomes
  • RNA, Small Interfering